The A3 adenosine receptor (A3AR) has significant roles in cardioprotection during ischemia/reperfusion (I/R) injury. However, current conflicting results suggest that some A3AR actions may also be deleterious to the ischemic myocardium possibly due to enhanced inflammatory responses. Accordingly, we predict that contradictory results from I/R injury models are due to opposing actions of cell-specific A3ARs within the heart. We hypothesize that it is essential that differential activities of A3ARs in the mouse myocardium are balanced to achieve maximum cardioprotection during I/R insults. Therefore, it is crucial to elucidate the cell-specific functions of A3ARs to determine which is important for cardioprotection. We will test this hypothesis by generating inducible myocyte-specific A3AR "knock-out" mice that will result in mice with A3AR expression in all tissues except in myocytes. We will also perform bone-marrow transplantation to generate mice that lack A3ARs only in bone marrow-derived cells and mice that express A3ARs only in bone marrow-derived cells. These resulting mice will be tested for the effects on infarct sizes during I/R insults utilizing whole animal studies to elucidate in which cells A3ARs are essential for cardioprotection.